Numerous studies implicate the ventral medulla (VM) in narcotic analgesia and stimulation produced-analgesia. Preliminary studies report for the first time a newly identified descending analgesia system originating in VM, the bulbospinal substance P (SP) system. The role of this newly identified descending SP analgesia pathway in pain inhibition will be explored in proposed recording studies. The ability of SP antagonists and serotonin (5-HT) antagonists to block VM inhibition of dorsal horn nociceptive units will be quantitatively assessed, allowing the quantification of the relative contributions of bulbospinal SP and 5-HT systems in pain inhibition. The unique design of the recording studies will permit primary afferent SP input to be contrasted with bulbospinal SP input to the same dorsal horn neuron. The interaction of the bulbospinal SP and 5-HT systems will also be explored in recording studies employing 5,7-DHT treated animals to selectively destroy spinal 5-HT fibers. In our working model the descending 5-HT system plays an important interactive role in bulbospinal SP-mediated pain inhibition. A second group of experiments are proposed to pharmacologically define the 5-HT receptor subtype associated with this bulbospinal 5-HT analgesia system. Proposed receptor binding and recording studies will pharmacologically characterize the 5-HT receptor subtype (1A or 1B) associated with the descending 5-HT analgesia pathway. Proposed receptor binding competition experiments will characterize dorsal horn 1A and 1B 5-HT receptor subtypes and identify the most selective 1A and 1B agonists and antagonists for use in subsequent recording studies. These recording studies will determine the 5-HT1 receptor subtype mediating inhibition of dorsal horn nociceptive unit activity. In addition to the importance of these studies for pain research, they will provide an understanding of receptor structure/function relationships rarely seen in the CNS.
